Cardiovascular burden of narcolepsy: what have we learned and what do we still need to know? Free

Narcolepsy is a rare central disorder of hypersomnolence characterized by excessive daytime sleepiness that can be associated with cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis, and disrupted nighttime sleep. Two forms of narcolepsy are identified: narcolepsy type 1 (NT1, formerly named narcolepsy with cataplexy) caused by a loss of orexinergic/hypocretinergic neurons in the hypothalamus and low cerebrospinal (CSF) orexin levels; and narcolepsy type 2 (NT2, formerly named narcolepsy without cataplexy) sometimes associated with partial loss of orexin neurons, but most often associated with normal CSF orexin levels and therefore of unknown pathophysiology [1].

The orexin system is involved in the central regulation of several basic functions, including the sleep–wake cycles but also the autonomic control (e.g. heart rate and blood pressure), thermoregulation, and energy homeostasis. NT1 is associated with clinical autonomic dysfunction, daytime hypertension, and a frequent lack of nocturnal blood pressure dipping [2–4], a phenomenon linked to mortality in the general population [5, 6]. Surprisingly, patients with NT1 had lower resting sympathetic and cardiovascular activities, assessed by direct microneurographic monitoring of muscle sympathetic nerve activity during wakefulness [7]. Also, patients with NT1 are often obese (30%–50%), with a weight gain especially in childhood and at disease onset [8, 9], with diabetes type 2, metabolic syndrome [10, 11], depression [12], and other sleep disorders (e.g. sleep apnea, periodic leg movements), which further increase their cardiovascular risk [3]. However, as key limitations, these results often come for small sample sizes, cross-sectional studies, mainly in NT1, and in patients often treated with wake-promoting agents (e.g. modafinil/armodafinil, solriamfetol, pitolisant, methylphenidate, and amphetamines), sodium oxybate and antidepressants/anticataplectic (e.g. venlafaxine, clomipramine, and fluoxetine) drugs. Most of these life-long medications, often used in both narcolepsy types, can affect the autonomic nervous system, especially by increasing heart rate and blood pressure [13]. Thus, causal links between Narcolepsy (NT1/NT2) and cardiovascular disorders were difficult to establish. More recently, patients with narcolepsy, without individualization of NT1 versus NT2, from different US-population-based analyses were reported to be associated with an increased risk of cardiovascular disorders (myocardial infarction, cardiac arrest, heart failure, and stroke) and an albeit controversial risk of increased mortality rate [11, 14, 15].

The good work by Ben-Joseph et al. in this issue of SLEEP [16] represents an important advance in the best of our knowledge of the relationship between cardiovascular health and narcolepsy, by revealing a higher incidence of new-onset cardiovascular events in adults with narcolepsy compared to controls. Through an observational retrospective cohort study utilizing a claims database, individuals with narcolepsy were found to be at a significantly elevated risk of various new-onset cardiovascular events, such as any stroke, heart failure, ischemic stroke, major adverse cardiac event, combined instances of stroke, atrial fibrillation, or edema, and cardiovascular disease when compared to non-narcolepsy controls. The study utilized a cohort design, with a very large sample size: 12 816 patients with narcolepsy (2948 with type 1 and 9868 with type 2) versus 38 441 controls. The non-narcolepsy control cohort was created by matching it to the narcolepsy cohort in a 1:3 ratio based on cohort entry date, age (38.3 years old), sex (67.1% female), geographic region, and insurance type. The authors used a multivariable Cox proportional hazards model to calculate adjusted hazard ratios and their corresponding 95% confidence intervals, estimating the relative risk of new-onset cardiovascular events, and adjusted for relevant factors, with final hazard ratios ranging from 1.30 to 1.71. Patients with narcolepsy had a higher prevalence of comorbidities at baseline, and the increased risk was not driven by the narcolepsy subtype. Whereas previous efforts aimed at determining the cross-sectional prevalence of cardiovascular comorbidities in people with narcolepsy [15, 17, 18], the present work quantified the longitudinal excess risk of new-onset cardiovascular events in narcolepsy, providing the first evidence that narcolepsy precedes the occurrence of cardiovascular comorbidities. This US population-based study has several notable strengths. An impressive large sample size was analyzed, that appears to be representative of the broader narcolepsy population in the United States, and the authors tried to avoid confounding factors by carefully matching patients to a control cohort on multiple characteristics and risk factors.

We may however question on the why and how of these associations. The relationship between cardiovascular risk factors, the risk of cardiovascular events in narcolepsy is complex and poorly understood [3]. It may involve multiple factors such as orexin deficiency (for NT1), disturbed nighttime sleep, excessive daytime sleepiness per se as reported in the general population [19], obesity, diabetes, high periodic limb movements and apnea–hypopnea indexes, depression, abnormal sleep architecture and continuity, and finally the medications intake for narcolepsy for several decades.

Several limitations to this work should be underlined. First, the effect of medication for narcolepsy on the cardiovascular system is critical and can explain a large part of the results obtained. However, these major data (treatment status, drugs and dosages, and duration of treatment) were not available in the study. Long-term data on cardiovascular outcomes associated with narcolepsy treatments are generally lacking. Second, in this study, the body mass index was not available, thus the controls were not body mass index-matched to patients, being however, often obese/overweight in the literature. Third, the large inclusion of patients with NT2 compared to NT1 is questionable, as are the diagnostic criteria for NT2 and its instability over time [20]. Fourth, a potential bias of selection of patients, inherent to their identification with an insurance claims database, with potential lack of generalizability to patients selected from sleep clinic, populations outside United States, and uncovered by insurance. These large registry-based studies were performed using records that did not include the results of clinical and neurophysiological examinations to formally confirm the diagnosis, assess the duration and severity of the disease, neither the CSF orexin levels, precluding analysis of any potential relationship between orexin deficiency and cardiovascular risk in narcolepsy. Finally, the authors do not propose any mechanistic hypothesis underlying this increased risk of cardiovascular diseases in NT1, and especially in NT2 with often normal orexin levels. Elevated cardiovascular risk in NT2 relative to the general population and greater than NT1 although in a lower population, would suggest a different mechanism than orexin deficiency. Considering all these limitations, these findings should be interpreted with caution; and the author themselves admit that additional research is needed in the field.

To conclude, the high incidence of new-onset cardiovascular events in patients with narcolepsy should encourage all physicians to carefully examine cardiovascular risk, to further consider treatment options and to reassess regularly the benefit-risk ratio of the drugs used in narcolepsy. The management of multiple health conditions in these patients should include regular assessment of cardiovascular health, including for instance the use of ambulatory blood pressure monitoring as we previously advocated [13].

Disclosure Statements

Financial disclosure: LB and YD report no competing interests related to this manuscript. Nonfinancial disclosure: LB received funds for traveling to conferences by Idorsia, and Bioprojet, and board engagements by Jazz, Takeda, Idorsia, and Bioprojet. YD received funds for seminars, board engagements, and travel to conferences by Jazz, Orexia, Idorsia, Takeda, Avadel, and Bioprojet.

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